Soat2 ties cholesterol metabolism to β-oxidation and glucose tolerance in male mice

J Intern Med. 2022 Aug;292(2):296-307. doi: 10.1111/joim.13450. Epub 2022 Jan 13.

Abstract

Background: Sterol O-acyltransferase 2 (Soat2) encodes acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2), which synthesizes cholesteryl esters in hepatocytes and enterocytes fated either to storage or to secretion into nascent triglyceride-rich lipoproteins.

Objectives: We aimed to unravel the molecular mechanisms leading to reduced hepatic steatosis when Soat2 is depleted in mice.

Methods: Soat2-/- and wild-type mice were fed a high-fat, a high-carbohydrate, or a chow diet, and parameters of lipid and glucose metabolism were assessed.

Results: Glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose tolerance (OGTT), and insulin tolerance tests significantly improved in Soat2-/- mice, irrespective of the dietary regimes (2-way ANOVA). The significant positive correlations between area under the curve (AUC) OGTT (r = 0.66, p < 0.05), serum fasting insulin (r = 0.86, p < 0.05), HOMA-IR (r = 0.86, p < 0.05), Adipo-IR (0.87, p < 0.05), hepatic triglycerides (TGs) (r = 0.89, p < 0.05), very-low-density lipoprotein (VLDL)-TG (r = 0.87, p < 0.05) and the hepatic cholesteryl esters in wild-type mice disappeared in Soat2-/- mice. Genetic depletion of Soat2 also increased whole-body oxidation by 30% (p < 0.05) compared to wild-type mice.

Conclusion: Our data demonstrate that ACAT2-generated cholesteryl esters negatively affect the metabolic control by retaining TG in the liver and that genetic inhibition of Soat2 improves liver steatosis via partitioning of lipids into secretory (VLDL-TG) and oxidative (fatty acids) pathways.

Keywords: ACAT2; CIDEC; GLUT2; NAFLD; Soat2; atherosclerosis; cardiometabolic diseases; cholesteryl esters; insulin resistance; lipoproteins; triglycerides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol Esters / metabolism
  • Fatty Liver* / metabolism
  • Glucose / metabolism
  • Insulins* / metabolism
  • Lipoproteins, VLDL / metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Sterol O-Acyltransferase 2
  • Sterol O-Acyltransferase* / genetics
  • Sterol O-Acyltransferase* / metabolism
  • Triglycerides

Substances

  • Cholesterol Esters
  • Insulins
  • Lipoproteins, VLDL
  • Triglycerides
  • Sterol O-Acyltransferase
  • Glucose